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<p>During restricted timeframes in <i>Drosophila</i> development, re-replication occurs as physiological process causing the known developmental gene amplification in <i>Drosophila</i>. Gene amplification has also been found during differentiation in human stem cells but re-replication in human cells has been preferentially associated with tumor related genome instability. Here, we show that re-replication also occurs as physiological process in human stem cells. We used Rerep-Seq and fiber-combing to demonstrate re-replication during the differentiation of human myoblasts into myotubes and during the differentiation of mesenchymal stem cells into adipocytes, osteoblasts, chondrocytes, and neurons. Re-replication was detectable during specific timeframes in all differentiations analyzed. FACS sorting of re-replicating cells showed increased gene expression in re-replicated genome regions. Additionally, re-replicated DNA was identified as extranuclear DNA. This leads us to the hypothesis that cells that do not re-replicate and thus do not face an increased risk of chromosomal instability may ensure higher expression of certain genes and their encoded proteins during differentiation by incorporating re-replicated DNA from neighbouring cells with re-replication. We propose that human stem cells use an ancient re-replication mechanism to efficiently increase gene copy numbers, thereby meeting the heightened protein demands during differentiation.</p>

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Physiological re-replication during human stem cell differentiation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月29日

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  • Marie Minet,
  • Amila Beganovic,
  • Shusruto Rishik,
  • Elisa Michaeli,
  • Daniela Yildiz,
  • Georges P. Schmartz,
  • Paula E. Schwarz,
  • Melina Schäfer,
  • Tanja Tänzer,
  • Magali Cucchiarini,
  • Nicole Ludwig,
  • Andreas Keller,
  • Eckart Meese,
  • Ulrike Fischer

摘要

During restricted timeframes in Drosophila development, re-replication occurs as physiological process causing the known developmental gene amplification in Drosophila. Gene amplification has also been found during differentiation in human stem cells but re-replication in human cells has been preferentially associated with tumor related genome instability. Here, we show that re-replication also occurs as physiological process in human stem cells. We used Rerep-Seq and fiber-combing to demonstrate re-replication during the differentiation of human myoblasts into myotubes and during the differentiation of mesenchymal stem cells into adipocytes, osteoblasts, chondrocytes, and neurons. Re-replication was detectable during specific timeframes in all differentiations analyzed. FACS sorting of re-replicating cells showed increased gene expression in re-replicated genome regions. Additionally, re-replicated DNA was identified as extranuclear DNA. This leads us to the hypothesis that cells that do not re-replicate and thus do not face an increased risk of chromosomal instability may ensure higher expression of certain genes and their encoded proteins during differentiation by incorporating re-replicated DNA from neighbouring cells with re-replication. We propose that human stem cells use an ancient re-replication mechanism to efficiently increase gene copy numbers, thereby meeting the heightened protein demands during differentiation.